Many low molecular weight drugs used in chemotherapy rapidly enter all types of cells by random diffusion through the cell membrane. This lack of selectivity decreases availability at the desired target cells or tissue and sometimes causes undesirable side effects. Cellular uptake is rapid so that the therapeutic effect is not extended over a period of time. Furthermore, glomerular filtration can rapidly remove the drugs from the bloodstream.
The covalent attachment of low molecular weight bioactive molecules to soluble polymeric carriers both prevents glomerular filtration and promotes cellular absorption by mechanisms other than just simple diffusion.
Synthetic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer is an example of a biocompatible, water-soluble, inert and neutral drug carrier for in vivo delivery of anti-cancer therapeutics (See, for example, U.S. Pat. Nos. 4,062,831 and 4,097,470). The conjugation of anticancer drugs to HPMA copolymers results in many advantageous features over small molecular therapeutics, including improved solubility and bioavailability, preferential accumulation of the conjugates in solid tumors or passive tumor targeting due to the enhanced permeability and retention (EPR) effect, reduced systemic toxicity and enhanced therapeutic efficacy, and down-regulation of multi-drug resistance.
There are currently six HPMA copolymer-drug conjugates at various stages of clinical trials and their preparation and compositions are disclosed in several patents. There are currently two polyglutamate-drug conjugates at various stages of clinical trials, and further polymer-drug conjugates including dextran-drug conjugates and PEG-drug conjugates are reported in clinical or preclinical development.
U.S. Pat. No. 5,037,883 issued Aug. 6, 1991, (Kopecek et al.) describes a drug conjugate of an inert polymeric carrier attached through a peptide linkage to bio-active molecules. This patent describes copolymers of N-(2-hydroxypropyl)methacrylamide containing oligopeptide sequences terminated in anticancer drugs (e.g. adriamycin, daunomycin, melphalan) and bound to targeting moieties (e.g. galactosamine, fucosylamine, anti-Thy 1.2 antibodies, anti-Ia antibodies) that are alleged to have a higher therapeutic efficacy compared to the low molecular weight drugs that contain no polymers. In particular a conjugate containing adriamycin as a drug (bound via a Gly-Phe-Leu-Gly oligopeptide sequence) and galactosamine as a targeting ligand is described. U.S. Pat. No. 6,692,734 (Stewart etc., 2004) and U.S. Pat. No. 7,166,733 (Nowotnik, 2007) describe a poly(HPMA)-GFLG-platinum drug. Luo et al. in US 2004/0234497 discloses a cell-targeted polymeric delivery system of poly(HPMA)-GFLG-HA-doxorubicin that was designed based on the specific interaction between hyaluronic acid (HA) and its cell surface receptors overexpressed on cancer cell surface. In US 2006/0014695, Ghandehari et al., also describes compositions and methods for nucleic acid delivery comprising HPMA conjugated to a polyamine. Another issued patent, U.S. Pat. No. 5,258,453 (Kopecek and Krinick, 1993) describes the combination effect of the anticancer agent and photoactivatable drug by poly(HPMA)-GFLG-adriamycin-ce6-secretin. Lammers et al. showed the delivery of two different chemotherapeutic agents (doxorubicin and gemcitabine) to tumors simultaneously using HPMA copolymers (Biomaterials 30: 3466-3475 (2009)).
There remains a need for additional polymer carriers for the delivery of anticancer drugs and the like.